Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated by reference herein as though set forth in full.
Chronic obstructive pulmonary disease (COPD), currently the fourth leading cause of death in the United States, is the only major leading cause of death that is increasing (1). Cigarette smoking is the most important cause and smoking cessation, early in the course of the disease, can slow the rate at which lung function is lost (2). While current therapies can help mitigate symptoms to some extent, no currently available medical therapy can restore lung function. Because of the relentless progression of the disease that occurs despite currently available therapies, COPD mortality will rise for the next several decades among those who previously smoked, even if cigarette smoking were to be eliminated from the population (3).
An abnormal inflammatory response of the lung, which persists despite cessation of smoking (4-7), is characteristic of COPD and inflammation is believed to play a major role in COPD pathogenesis (1, 8). The tissue alterations that underlie COPD result not only from tissue damage, but also from the inability of repair responses to restore tissue structure (1, 8, 9). In this context, cigarette smoke can directly inhibit repair processes (10-13). Inflammatory mediators can also modulate repair responses. Prostaglandin (PG) E2 is an inflammatory mediator that is increased in the lungs of COPD patients and is over-produced by COPD fibroblasts (14, 15). PGE2 is not only a biomarker for the inflammatory process in COPD, but also inhibits repair functions mediated by lung fibroblasts (16-20). When cultured ex-vivo, fibroblasts from COPD patients are deficient in a number of repair functions due, in part, to the over-production of PGE2.
PGE2, which is the major eicosanoid produced by fibroblasts, is released at low levels during basal conditions, but is released at much higher levels in response to a variety of stimuli including inflammatory mediators such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α that are believed to play roles in COPD. Thus, a clear need exists to determine the mechanisms driving PGE2 production by COPD in response to these inflammatory mediators, thereby providing new therapeutic strategies for the treatment of COPD and other pulmonary disorders.